Male contraceptive in development –

MADRID (EFE).—In 1960, the world’s population was regarding 3 billion inhabitants. Less than three decades later, in 1990, it exceeded 5 billion and in 2022 it reached 8 billion. And the trend continues: if projections are met, there will be 9 billion people in the world by 2037.

Although these figures reflect the urgent need to address global family planning, advances in contraception have been limited in recent decades and men still do not have oral contraceptives today.

Now, a team of researchers from Baylor College of Medicine and several collaborating institutions has demonstrated in animal models a novel, non-hormonal, sperm-specific method that might be a promising option for reversible male contraception in humans.

The details of the study were published yesterday in the journal “Science”.

“Although researchers have explored several strategies to develop male contraceptives, we do not yet have a birth control pill for men,” said Martin Matzuk, senior author of the study and professor in the Department of Pathology and Immunology at Baylor.

“In this study we focused on a novel approach: identifying a small molecule that inhibits serine/threonine kinase 33 (STK33), a protein essential for fertility in men and mice,” he notes.

Previous research has shown that STK33, which is found in the testicles, is necessary for the formation of functional sperm. In mice, if the Stk33 gene is deleted, they become sterile because they produce abnormal sperm with little motility.

In men, having a mutation in the STK33 gene causes infertility caused by the same sperm defects as those in mice without STK33 (called Stk33 knockout mice).

Importantly, mice and men with these mutations show no other defects and even have normal testicular size.

“Therefore, STK33 is considered a viable target with minimal safety concerns for contraception in men,” Matzuk says.

To date, STK33 inhibitors have been described, but none are specific to STK33 or potent enough to chemically disrupt STK33 function in living organisms. In this study, researchers have discovered potent STK33-specific inhibitors, from which they have successfully generated modified versions to make them more stable, potent and selective. “Of several of these modified versions, the compound CDD-2807 turned out to be the most effective,” says Angela Ku, first author of the paper.

The team tested the efficacy of CDD-2807 in their mouse model. “We tested various doses and treatment schedules and then determined sperm motility and number in the mice, as well as their ability to fertilize females,” said Courtney M. Sutton, a co-author and postdoctoral researcher in Matzuk’s group. The compound CDD-2807 reduced sperm motility, number, and fertility in the mice at low doses. Additionally, the team showed that the mice showed no signs of toxicity from CDD-2807 treatment, that the compound did not accumulate in the brain, and that the treatment did not alter testicular size, similar to STK33 knockout mice and males with the STK33 mutation.

“More importantly, the contraceptive effect was reversible. After a period without the CDD-2807 compound, the mice regained sperm motility and number and became fertile once more,” he said.

The team also presented the first crystal structure of STK33. “Our crystal structure shows how one of our potent inhibitors interacts with the STK33 kinase in three dimensions. This allowed us to model and design our final compound, CDD-2807, to obtain better drug-like properties,” said study co-author Choel Kim of Baylor.

The team will now continue to evaluate this STK33 inhibitor and compounds similar to CDD-2807 in primates to determine their efficacy as reversible male contraceptives.